The Hepatocyte Growth Factor Receptor, herein referred to as c-Met, is a receptor tyrosine kinase that has been shown to be over-expressed and/or mutated in a variety of malignancies, specifically, a number of c-Met mutations are found in various solid phase tumors. The c-Met ligand, hepatocyte growth factor (HGF), also known as scatter factor (SF), binds to c-Met in a pathway that is implicated in invasion and metastasis of tumor cells (Ma et al., 2003 Cancer and Metastasis Reviews. 22:309-325).
Interaction of HGF with c-Met initiates a cascade of intracellular events (Derman et al., 1996 J Biol Chem 23; 271(8):4251-4255). Binding of HGF results in activation of the intrinsic tyrosine kinase activity of c-Met and autophosphorylation of several tyrosine residues on the intracellular domain (Ma et al., 2003 Cancer and Metastasis Reviews. 22:309-325). Activation of the HGF/c-Met pathway results in a wide array of cellular responses including cell scattering, angiogenesis, proliferation, enhanced cell miotility, invasion and metastasis. Antagonism may act to inhibit autophosphorylation and/or to induce internalization of the surface cMet, and/or to down regulate cMet activity.
Tumor cells can invade a tissue boundary, degrading and remodeling the surrounding extracellular matrix, such that the tumor cells can migrate through the extracellular matrix tissue boundary permitting dissemination and formation of metastases. HGF/c-Met signaling is a pathway that mediates normal and malignant invasive growth. Missense mutations of c-Met have been identified in a variety of cancers, with most mutations located in the kinase domain. Mutants are characterized by increased tyrosine kinase activity thereby promoting the biological actions of c-Met.
There is need for compositions and methods to treat cancers, metastasis of cancers and inflammatory conditions, such as agents that interfere with HGF/c-Met signaling in which c-Metactivity contributes to invasion and/or metastasis.